Role of m5C-related regulatory genes in the diagnosis and prognosis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally, and is frequently associated with a poor prognosis. 5-methylcytosine (m(5)C) is a common epigenetic modification with many critical roles in eukaryotes. However, the expression and functional roles of m(5)C regulators are largely unknown. In this study, we utilized The Cancer Genome Atlas (TCGA) to determine the expression, gene signatures, and prognostic values of m(5)C-related genes. We confirmed that the frequency of mutation events of m(5)C regulatory genes was high in HCC (35/363). Dysregulation of m(5)C-related genes was also associated with a higher HCC stage. Moreover, a strong relationship was found between the expression of m(5)C regulatory genes and HCC patient survival. High expression of NSUN4 and ALYREF correlated significantly with survival outcome. We developed a two-gene signature of m(5)C regulators with HCC prognostic value based on the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models. Gene set enrichment analysis (GSEA) results indicated that high expression of NSUN4 was associated with methylation and demethylation processes. Meanwhile, high expression of ALYREF was clearly related to cell cycle regulation and mitosis. In conclusion, our results revealed that m(5)C-related genes play an essential role in tumor progression in HCC. Further detection of m(5)C methylation could provide a novel method for HCC targeted therapy.